Facio-brachio-crural dystonic episodes and drop attacks due to leucine rich glioma inactivated 1 encephalitis in two elderly Indian women Boby Varkey Maramattom, Sachin Rajashekar Jeevanagi, Celinamma George Department of Neurology, Lourdes Hospital, Kochi, Kerala, India Abstract Two women in their 60’s are presented to us with sudden falls of acute onset. Prolonged observation revealed a gradually evolving syndrome of paroxysmal right sided faciobrachial dystonic (FBD) posturing lasting seconds. Both patients went on to develop hyponatremia, following which the episodes worsened and appeared on both sides. In both cases, prolonged electroencephalography monitoring and magnetic resonance imaging brain were normal and the response to conventional anticonvulsants was poor. One patient improved spontaneously over 6 months. The 2nd patient developed an amnestic syndrome and was started on intravenous methylprednisolone with which her movement disorder abated. Her amnestic syndrome improved and she was discharged on oral steroids. Both patients tested positive for leucine-rich glioma inactivated 1 (LGi1) antibodies. We present the first case reports of FBD episodes and drop attacks owing to LGi1 encephalitis from India and review the relevant literature pertinent to the subject.
Key Words Anti-leucine-rich glioma inactivated 1 antibodies, drop attacks, faciobrachial dystonic seizures, leucine-rich glioma inactivated 1 encephalitis, paroxysmal non-kinesogenic dystonia For correspondence: Dr. Boby Varkey Maramattom, Department of Neurology, Lourdes Hospital,
Recently a new clinical syndrome, faciobrachial dystonic seizures (FBDS) has been characterized and associated with proteins associated with the voltage gated K+ channel (VGKC). This syndrome is specifically associated with antibodies to the leucine-rich glioma inactivated 1 (LGi1) protein. This LGi1 encephalitis is characterized by a peculiar movement disorder that often precedes that a florid amnestic syndrome. We present two elderly women that presented to us with frequent falls, sometimes mimicking drop attacks. Prolonged observation in hospital revealed the characteristic movements. Subsequent serum analysis revealed antibodies to LGi complex, substantiating the diagnosis of LGi1 encephalitis. This syndrome has not yet been described from India. We present the first cases of LGi1 encephalitis from India.
Case 1 A 68-year-old woman presented to us with sudden jerky right sided movements of 10 days duration that were also causing her to fall. These movements had started acutely and predominantly involved the right sided arm and leg. They occurred multiple times a day and initially were spontaneous and brief lasting a few seconds. They interfered with walking and caused frequent falls. Observation of a few of these episodes revealed facial grimacing and brief right upper limb dystonic posturing lasting 1-2 s. While standing or walking, the movements occasionally involved the right leg causing buckling at the knee and falls. There was no significant past medical history and routine investigations including prolonged electroencephalography (EEG) monitoring and magnetic resonance imaging (MRI) brain were normal. She was diagnosed with late onset paroxysmal non-kinesogenic dyskinesia (PNKD), likely symptomatic and was put on clonazepam, phenytoin without significant improvement. She was discharged after 5 days. After 1 month,
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See the Video on: www.annalsofian.org DOI: 10.4103/0972-2327.120480
Video 1: Video monitoring shows an initial left sided faciobrachial dystonic episode followed by two right sided event and then a right leg dystonic movement
Annals of Indian Academy of Neurology, October-December 2013, Vol 16, Issue 4
Maramattom, et al.: FBDS and drop attacks due to LGi1 encephalitis
she was readmitted from the emergency room with drowsiness and hyponatremia (serum sodium 116 meq/l). After correction of Na and improvement in sensorium, she was noticed to have frequent bilateral alternating attacks up to 30-50/day involving the face, arm and legs. Carbamazepine, lamotrigine and sodium valproate were added to her regimen. She had some symptomatic relief, but the episodes persisted. Her falls abated, but she continued to have mild faciobrachial dystonic (FBD) attacks. Serum was stored for future analysis. She declined to be video graphed and was requested discharge from our facility. At telephonic follow-up 6 months later, she was asymptomatic and off on all medications. Case 2 A 60-year-old woman was admitted to our ward with recurrent falls of 1 month duration. She was a long standing diabetic of 10 years duration on insulin and oral hypoglycemic agents. Her husband had noticed that she had developed a voracious appetite, eating every 2 h; although, there was no evident weight gain. For the past 3 days, the falls had increased in frequency and now she was falling 2-3 times a day. She complained of an abnormal sensation in the epigastrium followed by sudden buckling at the knee. She usually fell backward; although, she could fall to either side. On the day of admission, she had fallen 4 times and bruised her left side of the chest and sustained lacerations over the forehead and the occipital region [Figure 1]. She denied any palpitations or loss of consciousness during the episodes and was able to pick herself up immediately after the falls. There was no history of tongue bite or urinary or bowel incontinence associated with these episodes. She was admitted for further evaluation of drop attacks. Prolonged EEG monitoring was normal. Recurrent clinical episodes were recorded without any EEG correlate or recordable movement. MRI brain with contrast was normal. Holter monitoring was normal. Audiometry revealed mild sensorineural hearing loss bilaterally 1 week after admission; she continued to have recurrent falls with injury. Owing to hyponatremia (serum Na of 115 meq/l) and drowsiness, she was shifted to the intensive care unit for observation. At this time, she was noticed to have frequent brief alternating facial grimacing and upper limb dystonic posturing lasting a few seconds. Each of these episodes was preceded by the typical discomfort or aura that she experienced prior to fall and a
feeling of weightlessness. These episodes were now noticed to occur every time she became drowsy or woke up from sleep (approximately 30 times a day) [Video 1]. She was noticed to be very confused and disoriented. Her Addenbrooke’s cognitive examination (ACE) score was 68/100 with prominent deficits in attention, concentration and recall. Patient was treated with 1 g of intravenous (IV) methylprednisolone for 5 days followed by oral prednisolone 40 mg/day. She was shifted back to the ward where her husband continued to notice milder attacks with occasional posturing of the leg on the side of the attacks [Video 1]. The attacks gradually declined in frequency and by day 7 after initiation of therapy, she was asymptomatic and ambulant. Routine blood evaluation, liver function test, renal function test, thyroid function test and vasculitic work-up were normal. The cerebrospinal fluid study showed 0 cells and normal sugar and protein levels. Her ACE score had improved to 82/100. Serum was sent for anti LGi1 and contact in associated protein 2 (CASPR2) antibodies to Oxford University, UK. She tested positive for LGi1 antibody and negative for CASPR2. A second simultaneous sample sent to Statens Serum Institute Copenhagen was positive for LGi1 immunoglobulin G (IgG) antibodies at a titer of 1:320 and negative for LGi1 IgA & IgM, CASPR2, ANNA-1 (Hu), ANNA-2 (Ri), PCA-1 (Yo), Tr, Myelin-associated glycoprotein (MAG) antibody, myelin, PNMA1 (Ma/Tr), glutamic acid decarboxylase antibody (GAD), Amphiphysin, Aquaporin-4 (Aqp4), glycine receptor (GlyR), Abs, GABAbR, GluR (AMPA type) glutamate receptor and (GluR) (NMDA type) antibodies. Owing to financial constraints, the family declined further testing. She was discharged on oral prednisolone 40 mg/day. At follow-up 45 days later, there were no further falls or dystonic episodes; however, she complained of disabling persistent amnesia and her ACE score was 80/100 with predominant recent memory impairment. After review of the second case, serum of the 1st patient was sent to Oxford University for LGi1 and CASPR2 antibodies. Serum was positive for LGi1 antibodies and negative for CASPR2 antibodies.
Discussion This is the first report of FBD attacks from India. FBDS was first described with a male preponderance of 2:1. These attacks occur multiple times a day up to 50-70 times and are often brief lasting seconds, involving the face and arm and sometimes the leg. They often precede amnestic limbic encephalitis. Two types of FBDS have been described. Longer duration dystonic episodes are often associated with electrodecremental events (EDEs) on EEG that precede the events by around 500 ms. Shorter duration dystonic episodes are likely non-epileptogenic and do not have EEG correlates; thus, they are due to possible basal ganglionic dysfunction and fluoro-deoxyglucose-positron emission tomography can show basal ganglia dysfunction (hyper- or hypometabolism) even when the MRI is otherwise normal.
Figure 1: A left scalp laceration due to repeated falls
Recognizing this prodromal phase of FBDS is important as it is very immune-responsive to IV steroids or immunoglobulins. It is noteworthy that anticonvulsants are often ineffective even when used in combination and might even produce a hypersensitivity Annals of Indian Academy of Neurology, October-December 2013, Vol 16, Issue 4
592 Maramattom, et al.: FBDS and drop attacks due to LGi1 encephalitis
reaction such as Steven Johnson syndrome or erythroderma. Hence, it is imperative to recognize the immunotherapy responsiveness early. Often this is a primary autoimmune syndrome with antibodies to a cell membrane VGKC complex protein, specifically the LGi1 antibodies. The VGKC complex proteins include LGi1, CASPR2 and contactin 2. LGi1 protein is preferentially located within the hippocampus and may explain its association with the disease. CASPR2 and contactin 2 usually coexist together and are seen within the peripheral as well as the central nervous system, which might explain their association with neuromyotonia and Morvan’s syndrome.[2,3]
spontaneous faciobrachio-crural dystonic movements, which are unilateral or bilateral, hyponatremia, ictal EEG changes or EDEs or mesial temporal or basal ganglia abnormalities on MRI or an evolving amnestic syndrome. One should promptly test for LGi1 antibodies and consider early immunotherapy and paraneoplastic screening if necessary. Although optimal regimens are not yet identified, IV methylprednisolone, IV immunoglobuliins and plasma exchange have all been used. A small subset of patients might improve spontaneously as in our index case.  Relapses after successful treatment are rare.
A small subset of these patients (5%) harbors an underlying neoplasm, often a small cell lung carcinoma or a thymoma. MRI can be normal or show medial temporal hyperintensities or basal ganglia hyperintensities on T2-weighted images.
As the index case had unilateral non-kinesogenic paroxysmal choreoathetotic/dystonic movements at the onset, it resembled PNKD. The 2nd patient was thought to have drop attacks and investigated to rule out posterior fossa lesions, craniovertebral junction anomalies, cardiac arrhythmias, tumarkins otolithic crises and other etiologies. The diagnosis became clearer only when both patients had a similar clinical course with hyponatremia and then subsequently contralateral dystonic posturing. Perplexing features in our patients included the high number of falls; although, this is also well-described. In fact, backward falls were described in a large proportion of patients in the original series (62%), often unrelated to leg movements. Only prolonged observation and the emergence of the alternating pattern over time revealed the characteristic FBD in our cases. Our patients did not show any EEG changes consistent with ictal discharges or an electrodecremental pattern, suggesting the non-epileptic variant of FBDS. Clinicians should consider FBDS in the differential diagnosis of patients who present with PNKD choreoathetosis or drop attacks. Clues to this syndrome include brief paroxysmal
The authors would like to thank Clinical Immunology, Oxford University, UK. Gunnar Houen, Finn E. Somnier, MD, D.Sc. (M.Ed.) Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institute, Copenhagen, Denmark.
References 1. Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892-900. 2. Irani SR, Vincent A. Autoimmune encephalitis — New awareness, challenging questions. Discov Med 2011;11:449-58. 3. Serratrice G, Serratrice J. Continuous muscle activity, Morvan’s syndrome and limbic encephalitis: Ionic or non ionic disorders? Acta Myol 2011;30:32-3. 4. Kaymakamzade B, Kansu T, Tan E, Dericioğlu N. LGI1 related limbic encephalitis and response to immunosuppressive therapy. J Neurol 2011;258:2075-7.
How to cite this article: Maramattom BV, Jeevanagi SR, George C. Facio-brachio-crural dystonic episodes and drop attacks due to leucine rich glioma inactivated 1 encephalitis in two elderly Indian women. Ann Indian Acad Neurol 2013;16:590-2. Received: 17-03-13, Revised: 21-04-13, Accepted: 26-05-13
Annals of Indian Academy of Neurology, October-December 2013, Vol 16, Issue 4
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